There is compelling evidence that ?CD154 treatment has great potential in autoimmunity and graft rejection. Autoimmunity. Clinical efficacy of ?CD154 treatment has been seen in Lupus and idiopathic thrombocytopenia. In addition, Principal Investigator Dr. Noelle's clinical experience with ?CD154 is based on a Phase I trial in remitting/ relapsing MS. The results were striking: treatments over just 4 weeks resulted in: * No significant changes in Expanded Disability Status Scale from baseline for 5 years at all doses; * Improved Expanded Disability Status Scale correlated with increased dose and * Long-term follow up demonstrated a profound reduction in clinical relapse rate Graft Rejection. The remarkable feature of ?CD154 is that a brief treatment can instill long-term graft- specific tolerance, as demonstrated in NHP. This novel therapeutic will avoid the use of broad spectrum immunosuppressive drugs that create increased risk of cancer and infectious disease for the graft recipient. A treatment that results in long-term graft acceptance without life-long immunosuppression will lead to substantial benefits in quality of life, and substantially reduce the cost of treatment. Unfortunately, development of this exciting therapeutic was stalled by toxicity in some early clinical trials. Existing studies strongly suggest that domains within the Fc region of the ?CD154 mAb contribute to its toxicity and therapeutic capacity. When toxicity was observed in the clinic and retrospectively in NHP, modifications were made to the antibody. While these modifications eliminated toxicity in NHP, the efficacy of ?CD154 as a tolerogenic antibody also was significantly reduced. As a result, development programs for ?CD154 as a therapeutic stalled. The goal of this proposal is to generate variant forms of the ?murine CD154 antibody that will retain the beneficial tolerogenic effects of ?CD154 while greatly reducing or eliminating toxicity. Variant forms of the antibody will be evaluated in vivo using mouse models of transplantation and humoral immunity, as well as assessing their toxicity. Successful proof of concept in Phase 1 will be the basis for creating a similar variant of the human antibody in Phase 2 that will be developed as a novel therapeutic. To date, no one has engineered the specific changes proposed in this application. In the US, nearly 50 million people suffer from autoimmune diseases. Treatment costs over $100B/year. Over 20,000 US transplants are performed and over $500M/yr is spent on immunosuppression post-transplant. Our solution may help many patients in need.